Irritable Bowel Syndrome (IBS) is a functional bowel disorder of unknown etiology. A functional disorder refers to a disorder or disease where the primary abnormality is an altered physiological function, rather than an identifiable structural or biochemical cause. IBS is characterized by a group of symptoms including intermittent abdominal pain and discomfort and alterations in bowel habits, such as loose or more frequent bowel movements, diarrhea, and/or constipation that occur in the absence of detectable ongoing organic disease.
IBS affects approximately 10-20% of the general population. It is the most common disease diagnosed by gastroenterologists and one of the most common disorders seen by primary care physicians. EBS is understood as a multi-faceted disorder. In people with IBS, symptoms result from what appears to be a disturbance in the interaction between the gut or intestines, the brain, and the autonomic nervous system that alters regulation of bowel motility (motor function) or sensory function.
Human studies demonstrate that IBS is associated with a state of chronic visceral hypersensitivity (CVH) suggesting that processing of visceral sensory information is altered. However, little is known about how the afferent nervous system is changed in this syndrome. A hallmark of IBS is increased visceral hypersensitivity, but the molecular changes underlying the development and maintenance of chronic visceral hypersensitivity in IBS are not known. Current medical treatments for IBS primarily target peripheral symptoms rather than the underlying causes, and therapeutic gains from drug treatments are usually modest and the placebo responses are high (Mertz et al., Gastroenterology, 109:40-52, 1995). Defining the underlying neurological and molecular defects is therefore important to the design of more successful therapeutic strategies. Moreover, there is a need in the art for improved methods for screening, diagnosing, and treating IBS and other CVH-related disorders.
N,N′-bis[3,5-diacetylphenl] decanediamidetetrakis[amidinohydrazone] tetrahvdrochloride (CNI-1493) is a MAPK and TNF inhibitor with anti-inflammatory and possible analgesic actions. CNI-1493 inhibits signal transduction pathways by preventing phosphorylation of p38 MAP kinase and JNK, and inhibits production of the proinflammatory cytokines such as TNF-alpha, IL-1, IL-6, MIP-1 alpha and MIP-beta. In animal models, CNI-1493 has shown protective activity against a wide variety of conditions, ranging from stroke to inflammatory bowel disease. However, CNI-1493 has never been tested for its anti-nociceptive activity in the absence of inflammation. Recently, an animal model of chronic visceral hypersensitivity was created using mechanical and chemical irritation of the colon of neonatal rats (Al-Chaer et al., Gastroenterology, 119: 1276-1285, 2000). The animal model provides an ideal platform for studying IBS, validating the neurogenic components of functional abdominal pain, and testing agents that may reduce visceral hypersensitivity.